Despite decades of empiric research, lung adenocarcinoma remains America's leading cancer killer, with 86,000 deaths this year. Although tumor specimens from patients with this illness have a similar morphologic appearance, outcomes and sensitivity to treatment vary widely. Since molecular events underlie clinical observations, we hypothesize that unraveling mechanisms of lung adenocarcinoma maintenance, metastasis, and response to therapy will lead to the identification of therapeutic targets for the illness and for individual patients. Our experience in developing EGFR tyrosine kinase inhibitors (TKIs), and in the discovery that mutations in EGFR and KRAS genes underlie sensitivity and resistance to these agents, has demonstrated the practicality and potential of this approach. We propose 4 research projects and 3 core facilities all utilizing the same iterative research process uniting clinical and laboratory observations that have linked mutations in tumors to improved outcomes in patients. This grant embraces new investigators, technologies, and pathways. A specific clinical question focuses each project that proposes to identify targets for therapies in lung adenocarcinoma. RP1 proposes to find a gene signature responsible for brain metastases. These genes will serve as targets for intervention. RP2 attacks the problem of TKI-resistant, KRAS-driven tumors by determining their dependence on the downstream and parallel effectors BRAF, MEK/MAPK, and PIK3CA, which also represent targets for therapy. RP3 addresses the problem of EGFR-mutant cancers that persist despite TKI treatment. RP3 determines the "fate" of TKI-sensitive cells and elucidates mechanisms of survival and death of these malignant cells that can serve as targets for therapy. RP4 uses high throughput screening to discover therapeutic targets in KRAS- and EGFR-dependent cells. RP4 will also study the repertoire of proteins that interact with mutant and wild-type EGFR to identify additional targets. Our Molecular Profiling &Pathology Core A leverages years of experience in specimen collection, precise pathologic characterization in mouse and annotated human samples, mutation testing, and gene profiling in lung adenocarcinoma to enrich and support each project. The Information Engineering Core B and Administration &Analysis Core C will unify information storage and sharing, biostatistical analyses, and organization across the P01. They support the Executive and Advisory Committees to ensure rigorous scientific review, continuous reassessment of priorities, and rapid dissemination of our findings.